Norwitz, L6pez Bernal, and Starkey

Turnbull AC. Prostaglandins, chorioamnionitis and pre­term labour. Br J Obstet Gynaecol 1987;94: 1156-8.

19. Romero R, Wu YK, Brody D, Oyarzun E, DuffGW, Du­rum SK. Human decidua: a source of interleukin-1. Ob­stet Gynecol 1989;73:31-4.

20. Santhanam U, Avila C, Romero R, et al. Cytokines in normal and abnormal parturition: elevated amniotic fluid

September 1992 Am J Obstet Gynecol

interleukin-6 levels in women with premature rupture of membranes associated with intrauterine infection. Cyto­kines 1991;3:155-63.

21. Norwitz ER, Starkey PM, L6pez Bernal A. Prostaglandin D. production by term human decidua: cellular origins defined using flow cytometry. Obstet Gynecol 1992;80 [In press].

Physiologic baroreceptor activity in the fetal lamb

Akihiko Wakatsuki, MD, Yuji Murata, MD. Yuko Ninomiya, MD, Naoki Masaoka, MD, James G. Tyner, and Krishna K. Kutty

Orange, California

OBJECTIVE: We investigated the influences of gestational age and behavioral state on fetal baroreceptor activity.

STUDY DESIGN: Two protocols were used to analyze jow-voltage fast activity and high-voltage slow

activity in eight chronically instrumented ovine fetuses at. days 127 to 142. In protocol 1 correlation of fetal heart rate to mean arterial blood pressure was assessed under physiologic conditions, and the linear

regression slope of fetal heart rate on mean arterial pressure was calculated. In protocol 2 an injection of 7.5 I1g of norepinephrine was given during consecutive behavioral cycles. The ratio of fetal heart rate

decrease to mean arterial pressure increase was determined as representing baroreceptor activity.

RESULTS: Under protocol 1 the slope was steeper in high-voltage slow activity (2.33 ± 1.03) than in

low-voltage fast activity (0.89 ± 0.37) (n = 21, P < 0.001), indicating that fetal heart rate changes are sensitive to blood pressure changes during high-voltage slow activity. Under protocol 2 inverse

relationships were found between the ratio of fetal heart rate decrease to mean arterial pressure increase and gestational age in low-voltage fast activity and high-voltage slow activity.

CONCLUSION: Fetal baroreceptor activity increased during high-voltage slow activity and decreased with

gestational age. (AM J OaSTET GVNECOL 1992;167:820-7.)

Key words: Baroreceptor reflex activity, fetal lamb, behavioral state, gestational age

Heart rate decelerations have been frequently ob­served in human fetuses before 30 weeks' gestation,I.3 in animal fetuses born prematurely,. and in human neonates. 5 The mechanism of these decelerations may be reflex vagal nerve mediated! It has been reported that the increase in cholinesterase activity during ges­tation may help protect the mature fetus from severe bradycardia.4 The physiologic implications of fetal

From the Division of Maternal-Fetal Medicine, Department of Ob­stetrics and Gynecology, University of California, Irvine, College of Medicine, UCI Medical Center. Presented in part at the Thirty-eighth Annual Meeting of the Society for Gynecologic Investigation, San Antonio, Texas, March 20-23, 1991. Received for publication June 25, 1991, revised April 27, 1992; accepted May 4, 1992. Reprint requests: Yuji Murata, MD, Division of Maternal-Fetal M ed­icine, Department of Obstetrics and Gynecology, University of Cali­fornia, Irvine College of Medicine, UCI Medical Center, PO Box 14091, Orange, CA 92613-1491. 6/1/39052

820

heart rate (FHR) decelerations at early gestational ages and during the quiet behavioral state are not under­stood well enough to apply in clinical practice in peri­natal medicine.

The purpose of this study was to quantitatively eval­uate baroreceptor reflex activities at differing gesta­tional ages and behavioral states in chronically instru­mented fetal lambs.

Material and methods

Surgical preparation. The fetal lambs of eight time­mated Columbia-Rambouillet cross-bred sheep were chronically instrumented between 127 and 142 days' gestation (term 145 days).

All animals were maintained in a facility approved by the American Association for the Accreditation of Laboratory Animal Care and in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Before implementation research

Volume 167 Number 3

Baroreceptor activity in fetal lamb 821

Norepinephrine 7.5Jl1 1 min

-~ = E

120

! 60 ~ = ~

o

220

140

60

I I

Fig. 1. Arterial blood pressure (FBP) and FHR response after 7.5 flog norepinephrine bolus injection in the fetal lamb at 140 days of gestation.

protocols were approved by the Animal Research Com­mittee, University of California, Irvine.

After 24 hours of fasting, the ewe was given 12 to 14 mg xylazine (Rompun) anesthetic intramuscularly, with 1 % lidocaine used locally as needed. With the ewe in the lateral position the uterus was exposed by a mid­line abdominal incision. The fetal head was delivered through a hysterectomy incision and covered with a surgical glove filled with warm saline solution. Cathe­ters were inserted in the fetal carotid artery, jugular vein, and trachea. The electrodes for electrocardiog­raphy were sutured under the skin of the fetal thorax. Paired stainless steel screw electrodes were placed bi­laterally in the parietal skull for electrocardiogram re­cording. The FHR was obtained from the electrocar­diogram. An open-end catheter was placed in the am­niotic cavity to measure intrauterine pressure. Addi­tional catheters were placed in the maternal femoral artery and vein for blood pressure and drug admin­istration. All catheters and electrodes were exteriorized to the flank of the ewe.

Experimental procedure. The animals were kept in an air conditioned facility with food and water available as desired. Intravenous ampicillin (200 mg/kg per day) and gentamicin (6 mg/kg per day) were administered after surgery to mother and fetus, with ampicillin (1 gm/day) administered into the amniotic cavity for 3 to 4 days. Maternal and fetal arterial pH, blood gases, and hematocrits were checked daily. For the determi­nation of pH and gases approximately 0.6 ml of arterial

blood was collected anaerobically and measured by Corning pH/blood gas analyzer, model 168 BGA (Ciba Corning Diagnostics, Medfield, Mass.) at 37° C. Fetal well-being was determined by the following criteria: pH> 7.30, POe> 16 mm Hg, Peo. < 50 mm Hg, he­matocrit> 30%. Fetal arterial blood pressure, FHR, electrocorticogram, tracheal pressure, intrauterine pressure, and maternal blood pressure were continu­ously monitored after the surgery by polygraph (eight­channel rectilinear recorder, model R612, Sensor Med­ics, Anaheim, Calif.). Values of fetal blood pressure were corrected with intrauterine pressure as reference. Fetal behavioral states were analyzed from the electro­corticogram for low-voltage fast activity and high-volt­age slow activity.

Experiments were performed on or after the fifth postoperative day. All experiments were carried out between 9 AM and 5 PM with the ewe standing or lying quietly.

In five fetal lambs FHR and mean arterial pressure were measured every 30 to 60 seconds during stable physiologic periods of 1.5 hours when both low-voltage fast activity and high-voltage slow activity states alter­natively appeared. These states were determined ret­rospectively by electrocorticogram, and the measure­ments were taken at least 3 to 5 minutes after the start of a new state when these states were well established on electrocorticogram. A regression line for mean ar­terial pressure versus FHR was obtained. If the rela­tionship was statistically significant, the regression line

822 Wakatsuki et al.

200

180

E CI. e 160 0

c::.:: = 0 r-

140

CD 0

0 0

•

o

• •

o LVFA

• HVSA

o

September 1992 Am J Obstet Gynecol

120~~--~--~~~~--~--~~~~--~

30 35 40 45 50 55

MAP (mmHg)

Fig. 2. Relationship of FHR to mean arterial pressure (MAP) in high-voltage slow activity (HSVA) (closed circles) and low-voltage fast activity (LVFA) (open circles). Regression equations are as follows: LVFA: FHR = 245 - 2.01 (mean arterial pressure), r = 0.66, P < 0.00 I; high-voltage slow actiyity: FHR = 314 - 3.70 (mean arterial pressure), r = 0.88, P < 0.00 I.

Table I. Comparison of regression for FHR on mean arterial blood pressure of fetal lambs during low-voltage fast activity and high-voltage slow activity states

Sheep No.

89-16

89.17

89-18

90-05

90-06

Gestational age (days)

136 141 130 134 136 140 142 129 133 135 137 139 131 137 129 131 132 133 134 136 141

All are statistically significant at p < 0.01.

slope was considered to represent baroreceptor reflex activity.

In six fetal lambs 7.5 fLg of norepinephrine was in­jected intravenously during consecutive behavioral states (two to 10 times). At least 10 minutes elapsed between successive norepinephrine injections. The ra-

Low-voltage fast activity

-1.53 - 1.08 - 1.32 - 1.37 -0.98 - 1.25 -1.15 -2.01 - 1.00 -0.68 -0.41 -0.81 -0.80 -0.39 -1.00 -0.73 -0.81 -0.87 -0.78 -0.41 -0.37

Slope of regJ'essioll line

I High-voltage slow activity

-2.43 -2.22 -1.95 -1.38 -2.69 -3.49 -1.27 -3.70 - 1.88 -1.34 -1.63 -2.18 -0.93 -1.65 -2.88 -1.48 -1.94 -1.13 -1.94 -4.30 -2.64

tio of maximal FHR decrease to maximal mean arterial pressure increase (ilFHRI ilMAP) response to the nor­epinephrine injections (Fig. 1) was calculated to quan­titatively represent fetal baroreAex activity."

The standard dose of norepinephrine and the ilFHRI ilMAP ratio were aett'fminea from pilot ex-

Volume 167 Number 3

periments conducted on three fetal lambs at 127, 129, and 138 days' gestation, respectively. In these norepi­nephrine was injected at five doses (2.5, 5.0, 7.5, 10.0, and 15.0 J.1g). The relation between AFHR and AMAP and norepinephrine dosage in low-voltage fast activity and high-voltage slow activity states was ob­served.

Data analysis. The differences between low-voltage fast activity and high-voltage slow activity behavioral states were analyzed by paired t test and found signif­icant. The regression line was analyzed by the least­squares method, and regression slopes were compared by t test regression analysis. 7 Statistical significance was accepted at p < 0.05. All data were reported as mean ± SD.

Results

Fig. 2 demonstrates an example of the regression analysis of FHR on mean arterial pressure in both be­havioral states, with the slope of the regression line steeper during high-voltage slow activity than low-volt­age fast activity (p < 0.001, t test). Table I compares both behavioral states for five fetal lambs. All regression lines achieved statistical significance (p < 0.01). The high-voltage slow activity (2.33 + 1.03) slope is signif­icantly steeper than that of low-voltage fast activity (0.89 ± 0.37) (n = 21, P < 0.001).

In the basic norepinephrine dose-response experi­ment strong positive correlations were obtained be­tween AFHR and norepinephrine dosage (2.5, 5.0, 7.5, 10.0, and 15.0 ILg) in both behavioral states (Fig. 3). Similarly, strong positive correlations were found be­tween AMAP and norepinephrine dosage (Fig. 4). On the basis of these results, 7.5 ILg norepinephrine was selected as a standard dose because AFHR and AMAP at this level achieved approximately 50% of the maxi­mal norepinephrine dosage response. In addition, strong positive correlations were found between AFHR and AMAP in both behavioral states (Fig. 5). From this result the ratio of AFHR and AMAP was also used as an index of baroreceptor reflex function.

To assess tachyphylaxis of the response reflex, AFHR, AMAP, and the ratio of AFHR/AMAP were compared for the first and last norepinephrine injec­tion in both behavioral states. No significant difference (paired t test) was found between the values for the first and last norepinephrine injection (Table II).

Fig. 6 shows the ratio of AFHR/ AMAP in response to sequential standard norepinephrine injections for each animal. In 80 observations the ratio was signifi­cantly higher in high-voltage slow activity (2.73 ± 0.74 beats/min per 1 mm Hg) than in low-voltage fast ac­tivity state (1.85 ± 0.78 beats/min per I mm Hg) (p < 0.00 I, paired t test). Significant inverse rela­tionships were found between the AFHR/ AMAP

8' =-e ~ :::: ... <l

100

80

60

40

20

0 0.0

100

80

20

Baroreceptor activity in fetal lamb 823

D

2.5

LVFA State

D 138 days: r=O.90 pdl.05

• 135 days: r=O.98 p<O.OO5

o 129 days: r=O.99 p<O.OOI

5.0 7.5 10.0

NE Dosage (~g)

HVSA State

g 138 days: r=O.98 p<O.OO5

• 135 days: r=O.98 p<O.OO5

o 129 days: r=O.91 p<O.Ol

12.5 15.0

o~ __ ~ ____ ~ __ ~ __ ~ ____ ~ __ ~ __ _ 0.0 2.5 5.0 7.5 10.0 12.5 15.0

NE Dosage (~g)

Fig. 3. Relationship between 8FHR and norepinephrine (NE) doses (2.5, 5.0, 7.5, 10.0, and 15.0 f.Lg) in low-voltage fast activity (LVFA) and high-voltage slow activity (HSVA) state for three different fetal lambs.

ratio and gestational age III both behavioral states (Fig. 7).

Comment

Several investigators have confirmed the fall of FHR attributable to baroreceptor mechanisms·olO and that baroreceptor activity was present as early as 85 days of gestation.· Dawes et al. 1I reported that in the human the presence of decelerations during 28 to 41 weeks of gestation was common (18%) in records with normal neonatal outcome.

To determine the baroreceptor reflex function, two techniques were used in this study. First, in observations

824 Wakatsuki et al.

40

30

i'iI 1 20

~ 10

LVFA State

D 138 days: r=O.94 p<O.OI

• 135 days: r=O.96 p<O.OI

o 129 days: r=O.98 p<O.OO5

O~ __ ~ __ ~ __ ~~ __ ~ __ -L __ ~ __ __

0.0 2.5 5.0

40

30

10

7.5 10.0 12.5 15.0

NE Dosage (Ilg)

HVSA State

o

c 138 days: r=O.94 p<O.OI

• 135 days: r=O.97 p<O.OI

o 129 days: r=O.96 p<O.OI

O~ __ ~ __ ~ ____ ~ __ ~ ____ ~ __ ~ __ _

0.0 2.5 5.0 7.5 10.0 12.5 15.0

NE Dosage (Ilg)

Fig. 4. Relationship between ~MAP and norepinephrine (NE) doses (2.5, 5.0, 7.5, 10.0 and 15.0 f.Lg) in low-voltage fast ac­tivity (LVFA) and high-voltage slow activity (HVSA) state for three different fetal lambs.

of mean arterial pressure and FHR under physiologic conditions the slope of a linear regression line of FHR on mean arterial pressure was assessed. The slope was steeper in the high-voltage slow activity than in the low­voltage fast activity state. This result suggests that baro­receptor reflex function is higher in the high-voltage slow activity than in the low-voltage fast activity state.

In 1980 Dawes et al. '2 reported the threshold for baroreceptor response to be above the range of the normal fetal arterial pressure. They suggested that baroreflexes would be elicited only by a large change

100

80

i 60

e cr:: 40 == '-<l

20

o

100

80

E 60 Q, e

cr:: 40 is <l

20

0 0

September 1992 Am J Dbstet Gynecol

LVFA State

c 138 days: r=O.96 p<O.OO5

• 135 days: r=O.99 p&.OO5

0 129 days: r=O.99 p<O.OOI

10 20

dMAP (mmHg)

HVSA State

c 138 days: r=O.98 p<O.OO5

• 135 days: r=O.97 p<O.OI o 129 days: r=O.99 p<O.OOI

10 20

dMAP (mmHg)

30 40

30 40

Fig. 5. Relationship between ~FHR and ~MAP (2.5, 5.0, 7.5, 10.0, and 15.0 f.Lg) in low-voltage fast activity (LVSA) and high­voltage slow activity (HSVA) state for three different fetal lambs.

in pressure and would not be important factors in normal physiologic FHR regulation or in buffering blood pressure in fetal life. In contrast, Itskovitz et al. 13 concluded that arterial baroreceptors play

an important role in regulating fetal circulation even under normal physiologic conditions. In the current study the linear regression between FHR and mean arterial pressure during physiologic conditions dem­onstrated that there is active baroreceptor regulation of the fetal cardiovascular system under physiologic conditions.

The relationship between cardiac rhythm and arte-

Volume 167 Number 3

en :c E E E

Co e Q.,

< ::; ~ CI: :c .... <l

5

4

3

2

0

Baroreceptor activity in fetal lamb 825

HV HV HV HV HV HV LV LV LV LV LV LV LV

Fig. 6. Ratio of 6.FHR to 6.MAP in response to 7.5 ILg norepinephrine injection to six animals at sequential behavioral states for each animal (high-voltage [HV] high-voltage slow activity; low-voltage [LV] , low-voltage fast activity). Ratio was significantly greater in high-voltage slow activity state (P < 0.001 , paired t test, 80 pairs).

Table II. Values of ~FHR, ~MAP, and ~FHR/ ~MAP ratio at first and last norepinephrine injections during low-voltage fast activity and high-voltage slow activity states

Low-voltage fast actil1it.v High-voltage slow aclivit)'

6.FHR (beats /min) 6.MAP (mm Hg) 6.FHR /6.MAP

(beats /min per 1 mm Hg)

Values are mean ± SD.

n

15 15 15

First norepinephrine

4 1.00 ± 13.77 22.54 ± 6.07

2.07 ± 0.99

rial blood pressure has been examined as an indicator of baroreceptor reflex functions in human'" 15 and animal6. R. 9. 12 . ... 16·19 studies. A number of workers have

studied baroreceptor behavior in the fetal and neonatal lamb.s.9. 12. 13. 16 The ratio of ~FHRI ~MAP after a-sym­pathetic stimulator injection has been confirmed to in­dicate baroreceptor reflex activi ty.6 Norepinephrine may exert direct l3-adrenergic effects on the myocar­dium. In the current study use of norepinephrine to elevate blood pressure resulted in a significant positive correlation between ~FHR and ~MAP at all norepi­nephrine dose levels. Wang and Borison20 reported that the earliest component influencing heart rate was vagus and that the sympathetic component developed more slowly. According to Coleman," pressor drug injection produced vagal reflex deceleration 1 second after the maximum blood pressure response, and this change in heart rate occurred before any appreciable l3-sympa­thetic component developed. There appears to be little

I Last

norepineph1'ine

39.67 ± 8.76 21.32 ± 5.24

2.09 ± 0.96

First norepinepln-ine

59.75 ± 17.88 2 1.54 ± 5. 19

3.08 ± 1.63

I Last

nm'epinephrine

57.06 ± 12.37 20.8 1 ± 5.44

3.06 ± 1.29

or no norepinephrine ~-adrenergic contribition in the ratio.

Norepinephrine injection was repeated two to 10 times during sequential behavioral states. To examine for tachyphylaxis , ~FHR, ~MAP, and the ratio of ~FHR/ ~MAP for first and last norepinephrine injec­tions were compared. The absence of significant dif­ferences suggests minimal possibility of norepineph­rine tachyphylaxis in the current study.

In 80 observations the ratio was significantly higher in the high-voltage slow activity than in the low-voltage fas t activity state. This suggests that the sensitivity of baroreceptor regulator function is higher in the high­voltage slow activity state. Dawes et al. ' 2 estimated baro­receptor sensitivity as the slope of heart period on ar­terial blood pressure produced by either balloon infla­tion or pressor drugs. The values they obtained did not differ during the low-voltage fast activity and high­voltage slow activity state. However, Zhu and Szeto"

826 Wakatsuki et al.

5

~ 4 ::c s i Q, 3 e

• I :

130 135 140

LVFA HVSA

145

September 1992 Am J Obstet Gynecol

Gestational Age (Days)

Fig. 7. Relationship between aFHRI aMAP and gestational age in low-voltage fast activity (closed circles) and high-voltage slow activity (open circles). Low-voltage fast activity: aFHRI aMAP = 24.60 - 0.17(gestational age), n = 53, P < 0.001; high-voltage slow activity: aFHR/aMAP = 19.00 - 0.12(gestational age), n = 52, P < 0.001.

observed FHR and mean arterial pressure after a-ad­renergic receptor blocker infusion and speculated that baroreceptor sensitivity was increased during the high­voltage slow activity state in the fetal lamb. Moreover, Baccelli et al. 22 reported that the baroreceptor reflex was diminished in rapid-eye-movement sleep in the adult cat.

The ratio decreased significantly with gestational age in both behavioral states, thus suggesting that barore­ceptor reflex activity decreases as gestational age ad­vances. A number of studies have reported variable results as to the sensitivity of the fetal baroreceptor at different gestational ages. Shinebourne et al." ex­pressed fetal baroreceptor as the slope of the relation­ship of blood pressure change elicited by balloon infla­tion and R-R interval or heart rate and reported that sensitivity increased through gestation. Maloney et al.9

found no gestational change of baroreceptor sensitivity with aortic balloons; however, the sensitivity was less in the neonate than in the fetus. Other investigators also detected no gestational change in baroreceptor sensi­tivity but concluded that the sensitivity was less in the fetus than in the neonate l2 or adult.!O

In the recent studies Blanco et aJ.23 recorded carotid sinus nerve activity in the fetal lamb. They used occlu­sion of the aorta to elicit baroreflex response and re­ported that the steep slope demonstrating the relation­ship between mean nerve discharge frequency and mean blood pressure decreased throughout the mea­surement periods (88 to 144 days' gestation, 1 to 40 days in the neonatal period). Scroop et al. 16 assessed baroreceptor function by analyzing the response of ar-

terial blood presusre to angiotensin II with correspond­ing changes in heart rate or R-R period and concluded that baroreceptor sensitivity was less in the neonate than in the fetus. These reports are consistent with the results of the current study. Drug-induced blood pres­sure changes show an increase with advancing neonatal age and during the transition from fetus to neonate." Drug-induced changes in blood pressure may result from modification of baroreceptor reflex function dur­ing fetal to neonatal development. However, the mech­anism for the difference of fetal baroreceptor reflex function reported in the current study is still unclear. Other studies have reported that reduced baroreceptor sensitivity was observed with various forms of hyper­tension in both animaJ25 and human I' and that this usu­ally has been considered a secondary phenomenon re­sulting from prolonged exposure to hypertension. In addition, several reports have shown that volume load­ing reduced baroreceptor sensitivity.17 During the fetal period arterial blood pressure and blood volume in­crease with gestational age. In the current study a pos­itive correlation was obtained between arterial blood pressure and gestational age, no doubt reflecting a pro­cess of continuing change of baroreceptor feedback control and sensitivity during fetal life. Many studies have reported a correlation between fetal arterial blood pressure and behavioral states, and some have con­cluded fetal mean arterial blood pressure was higher during the high-voltage slow activity than during the low-voltage fast activity state.26,27 According to Zhu and Szeto,21 however, no significant difference in arterial blood pressure was found between high-voltage slow

Volume 167 Number 3

activity and low-voltage fast activity behavioral states. In the current study, similar to their report, no signif­icant difference was observed between these behavioral states. The observed difference of baroreceptor sen­sitivity in both behavioral states remains to be ex­plained.

REFERENCES

I. Swartwout JR, Campbell WE, Williams LG. Observations on the fetal heart rate. AM J OBSTET GVNECOL 1961;82:301-3.

2. Wheeler T, Murrillis A. Patterns of fetal heart rate during normal pregnancy. BrJ Obstet GynaecoI1978;85:18-27.

3. Sorokin Y, Dierker LJ, Pillay SK, Zador IE, Schreiner ML, Rosen MG. The association between fetal heart rate pat­terns and fetal movements in pregnancies between 20 and 30 weeks' gestation. AM J OBSTET GVNECOL 1982;143: 243-9.

4. Maurer M Jr. Developmental factors contributing to the susceptibility to bradycardia in isolated, cultured fetal mouse hearts. Pediatr Res 1979;13:1052-7.

5. Kattwinkel J, Fanaroff AA, Klaus MH. Bradycardia in pre term infants: indications and hazards of atropine ther­apy. Pediatrics 1976;58:494-9.

6. Coleman TG. Arterial baroreflex control of heart rate in the conscious rat. Am J Physiol 1980;238: H515-20.

7. Glantz SA. How to test for trends. In: Barry BK, White J, eds. Primer of biostatistics. New York: McGraw-Hili, 1987.

8. Shinebourne EA, Vapaavouri EK, Williams RL, Heymann MA, Rudolph AM. Development of baroreflex activity in unanesthetized fetal and neonatal lambs. Circ Res 1972;31 :710-8.

9. Maloney JE, Cannata J, Dowling MH, Else W, Ritchie B. Baroreflex activity in conscious fetal and neonatal lambs. Bioi Neonatal 1977;31:340-50.

10. Ismay MJ, Lumbers ER, Stevens AD. The action of an­giotensin II on the baroreflex response of the conscious ewe and the conscious fetus. J Physiol (Lond) 1979;288:467-79.

II. Dawes GS, Houghton CR, Redman CW, Visser GH. Pat­tern of the normal human fetal heart rate. Br J Obstet Gynaecol 1982;89:276-84.

12. Dawes GS, Johnston BM, Walker DW. Relationshiop of arterial pressure and heart rate in fetal, new-born and adult sheep. J Physiol (Lond) 1980;309:405-17.

13. Itskovitz J, LaGamma EF, Rudolph AM. Baroreflex con-

Baroreceptor activity in fetal lamb 827

trol of the circulation in chronically instrumented fetal lamb. Circ Res 1983;52:589-96.

14. Wasserstrum N, Kirshon B, Rossavik IK, Willis RS, Moise KJ Jr, Cotton DB. Implications of sino-aortic baroreceptor reflex dysfunction in severe preeclampsia. Obstet Gynecol 1989;74:34-9.

15. Smyth HS, Sleight P, Pickering GW. Reflex regulations of arterial pressure during sleep in man. Circ Res 1969;24: 109-21.

16. Suoop GC, Marker JD, Stankewytsch-Janusch B, Sea­mark RF. Angiotensin I and II in the assessment of baro­receptor function in fetal and neonatal sheep. J Dev Phys­ioI1986;8:123-37.

17. Vatner SF, Boettcher DH, Hendrickx GR, McRitchie RJ. Reduced baroreflex sensitivity with volume loading in conscious dogs. Circ Res 1975;37:236-42.

18. Gardiner SM, Bennett T, Kemp PA. Systemic arterial hy­pertension in rats exposed to short-term isolation; intra­arterial systolic and diastolic blood pressure and barore­flex sensitivity. Med Bioi 1980;58:232-9.

19. McRitchie RJ, Vatner SF, Heyndrickx GR, Braunwald E. The role of arterial baroreceptors in the regulation of arterial pressure in conscious dog. Circ Res 1976;39:666-70.

20. Wang SC, Borison HL. An analysis of the carotid sinus cardiovascular reflex mechanism. Am .I Physiol 1947; 150:712-21.

21. Zhu YS, Szeto HH. Cyclic variation in fetal heart rate and sympathetic activity. AM .I OBSTET GVNECOL 1987; 156:1001-5.

22. Baccelli G, Albertini R, Mancia G, Zanchetti A. Interac­tions between sino-aortic reflexes and cardiovascular ef­fects of sleep and emotional behavior in the cat. Circ Res 1976;38 (suppl 2):30-4.

23. Blanco CE, Dawes GH, Hanson MA, McCooke HB. Ca­rotid baroreceptor in fetal and newborn sheep. Pediatr Res 1988;24:342-6.

24. Woods JR Jr, Dandavino A, Murayama K, Brinkman CR III, Assali NS. Autonomic control of cardiovascular func­tions during neonatal development and in adult sheep. Circ Res 1977;40:401-7.

25. Fletcher PJ. Baroreceptor heart rate reflex in rabbits after reversal of renal hypertension. Am J Physiol 1984;246:H261-6.

26 . .lost RG, Quilligan EJ, Yeh SY, Anderson CG. Intrauterine electroencephalogram of the sheep fetus. AM .I OBSTET GV:-.IECOL 1972;114:535-9.

27. Mann LI, Duchin S, Weiss RR. Fetal EEG sleep stages and physiologic variability. AM .I OBSTET GVNECOL 1974; 119:533-8.